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Tumor Discovery CDK4/6 inhibitor resistance in breast cancer

inhibitor, blocks MAPK pathway activation by inhibiting resistant tumors. Inhibition of cyclin E-CDK2 signaling
mutated BRAF kinase activity (e.g., V600E and V600K has demonstrated potential in overcoming resistance to
mutations). Resistance mechanisms include upregulation CDK4/6 inhibitors in certain cases. Other promising
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of CDK4 and cyclin D1, which bypass CDK4/6 inhibition targets implicated in resistance include components of the
and reactivate cell cycle progression. Pre-clinical models MAPK pathway, AURKA, and cyclin E. 15,28 These strategies
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have demonstrated that combining dabrafenib with aim to prolong the effectiveness of CDK4/6 inhibitors and
CDK4/6 inhibitors significantly reduces tumor growth improve patient outcomes in resistant tumors. Continued
by simultaneously targeting the MAPK and cell cycle research and clinical trials are expected to refine these
pathways. This dual inhibition prevents compensatory methodologies and may reveal additional strategies to
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activation of cyclin D1–CDK4 signaling, which is a key counteract resistance.
driver of dabrafenib resistance.
Cobimetinib is a selective MEK1/2 inhibitor that 6. Treatment options following CDK4/6
blocks downstream ERK activation in the MAPK pathway. inhibitor resistance
Resistance to cobimetinib often involves reactivation The selection of subsequent treatments after resistance to
of ERK further downstream or activation of parallel CDK4/6 inhibitors poses a significant challenge. Several
pathways, such as PI3K/AKT. Pre-clinical studies suggest strategies are being explored to optimize outcomes for
that combining cobimetinib with CDK4/6 inhibitors patients with HR-positive/HER2-negative breast cancer.
enhances anti-tumor efficacy by simultaneously targeting One common approach involves switching endocrine
both MAPK and cell cycle pathways. This combination is agents, such as transitioning from an AI to fulvestrant, or
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particularly effective in tumors with cyclin D1 amplification vice versa, which may provide clinical benefits in some
or p16INK4a loss. Trametinib is an allosteric MEK1/2 cases. 39,41 In addition, the combination of exemestane and
inhibitor that prevents phosphorylation and activation everolimus has shown efficacy in patients who progressed
of ERK, effectively blocking MAPK signaling. Resistance on CDK4/6 inhibitors, with median PFS ranging from 4.2
mechanisms include reactivation of the MAPK pathway or to 5.8 months across various studies. 42
compensatory activation of alternative survival pathways, For targeted therapies, PI3K inhibitors, such as alpelisib
such as PI3K/AKT/mTOR. The combination of trametinib combined with fulvestrant, have demonstrated a median
with CDK4/6 inhibitors has demonstrated synergistic PFS of 5.6 – 8.0 months in patients with PIK3CA mutations
effects in pre-clinical models by inhibiting both MAPK following CDK4/6 inhibitor treatment. 42,43 Similarly, AKT
and cell cycle pathways. 37,38 This dual inhibition restores inhibitors, such as capivasertib plus fulvestrant have
sensitivity to trametinib-resistant cells by suppressing shown a median PFS of 5.5 months in AKT-altered tumors
proliferation and inducing apoptosis. following CDK4/6 inhibitor treatment. Emerging evidence
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An emerging approach involves combining CDK4/6 also supports continuing the same CDK4/6 inhibitor while
inhibitors with immunotherapy to enhance anti-tumor switching the endocrine partner in select cases. 42,44 Limited
immunity. This combination increases T-cell infiltration data suggest potential benefits in switching to a different
and activation within the tumor microenvironment. CDK4/6 inhibitor, such as abemaciclib, after progression
Clinical trials are currently underway to assess the efficacy on palbociclib or ribociclib. 42
of this combination across various cancer types. 28 Innovative therapies are under investigation for
Sequential therapeutic approaches systematically resistant breast cancer. Antibody-drug conjugates and poly
administer various treatments to optimize therapeutic ADP-ribose polymerase inhibitors have shown promise
efficacy and delay resistance. For example, the sequential in clinical trials. 45,46 Chemotherapy remains an option for
application of CDK4/6 inhibitors and endocrine therapy patients with a visceral crisis or rapid disease progression,
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may mitigate or postpone resistance development. Novel although it is generally less favored due to its toxicity
CDK inhibitors are under development to address the profiles. 42,47 Recent studies indicate that trastuzumab
limitations of existing CDK4/6 inhibitors by offering deruxtecan is a viable alternative for HR-positive, HER2-
enhanced selectivity and potency. These inhibitors aim to low, or HER2-ultra-low metastatic breast cancer patients
demonstrate efficacy against tumors that have developed who have received one or more lines of endocrine therapy.
resistance. In addition, dual inhibitors targeting multiple This agent has achieved a median PFS of 13.2 months,
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CDKs and other cell cycle regulatory kinases are being approximately five months longer than chemotherapy. 48
investigated as potential strategies to overcome resistance. 40 The optimal sequencing of treatments after CDK4/6
A pivotal strategy involves identifying and targeting inhibitor resistance continues to evolve. Treatment
alternative pathways that sustain cell proliferation in selection should be personalized based on prior therapies,

Volume 4 Issue 1 (2025) 32 doi: 10.36922/td.7107